World Allergy Forum Symposium: the Application of Monoclonal Therapies and Therapeutics to Asthma and Allergy

World Allergy Forum Symposium: The Application of Monoclonal Therapies and Therapeutics to Asthma and Allergy

2008 AAAAI Annual Meeting Sunday, 16 March 2008 10:45 a.m. – 12:00 p.m. Philadelphia Convention Center Room 114, Street Level Philadelphia, PA, USA Moderators: G. Walter Canonica, MD Thomas B. Casale, MD FAAAAI Designer Drug Design: How are Monoclonal Antibodies Made in 2008? www.worldallergy.org Shyam S. Mohapatra, PhD FAAAAI

Adverse Effects in the Application of Biotechnology Programed by the Jean Bousquet, MD FAAAAI The Future Application of Monoclonal Antibodies to Asthma and Allergy Stephen T. Holgate, MD DSc FAAAAI

Supported through an unrestricted educational grant from The World Allergy Organization (WAO) is an international organization of 77 regional and national allergy and clinical immunology societies. WAO’s mission is to be a global resource and advocate in the field of allergy, advancing excellence in clinical care through education, research and training as a world-wide alliance of allergy and clinical immunology societies.

“The Application of Monoclonal Therapies www.worldallergy.org and Therapeutics to Asthma and Allergy”

Program Moderators: G. Walter Canonica, MD University of Genoa Genoa, Italy

Thomas B. Casale, MD FAAAAI Creighton University Omaha, NE, United States

1. Welcome to the World Allergy Forum Symposium and Introduction to “The Application of Monoclonal Therapies and Therapeutics to Asthma and Allergy” G. Walter Canonica and Thomas B. Casale 2. Designer Drug Design: How are Monoclonal Antibodies Made in 2008? Shyam S. Mohapatra, PhD FAAAAI University of South Florida Tampa, FL, United States 2. Adverse Effects in the Application of Biotechnology Jean Bousquet, MD FAAAAI Hôpital Arnaud De Villeneuve Montpellier, France 3. The Future Application of Monoclonal Antibodies to Asthma and Allergy Stephen T. Holgate, MD DSc FAAAAI Southampton General Hospital Southampton, United Kingdom Upon completion of this session, participants should be able to: Discuss the basic science of the hybridoma technique; Describe the reasons for failure of monoclonal antibody treatment; Describe the potential application of monoclonal antibody technology to asthma and allergy. 2008-2009 World Allergy Form Advisory Board Chair G. Walter Canoncia, Italy Vice Chair Richard F. Lockey, United States Core Advisors Advisors-at-Large Carlos Baena-Cagnani, Argentina Takeshi Fukuda, Japan Jean Bousquet, France Bee-Wah Lee, Singapore Thomas B. Casale, United States Jorge Maspero, Argentina Roy Gerth van Wijk, Netherlands Klaus Rabe, Netherlands Stephen T. Holgate, United Kingdom Larry Rosenwasser, United States Michael A. Kaliner, United States Pakit Vichyanond, Thailand Ruby Pawankar, Japan

About the World Allergy Organization World Allergy Organization (WAO) The World Allergy Organization (WAO) is an international umbrella organization of 77 regional and national allergy and clinical immunology societies. By collaborating with member societies, WAO provides direct educational outreach programs, symposia and lectureships to WAO individual members around the globe.

The World Allergy Organization Mission To be a global resource and advocate in the field of allergy, advancing excellence in clinical care through education, research and training as a world-wide alliance of allergy and clinical immunology societies. www.worldallergy.org

Programs of the World Allergy Organization

World Allergy Forum (WAF) www.worldallergy.org/waf www.worldallergy.org/gloria WAF symposia are held at major international allergy meetings. Developed The GLORIA program promotes good practice in the by international expert advisory panels, management of allergic diseases through programs developed by the symposia provide up-to-the-minute panels of world experts. GLORIA educates medical professionals presentations on scientific and clinical worldwide through regional and national presentations and local developments in the field of allergic disease. training initiatives. GLORIA educational modules promote the World Allergy Organization’s (WAO) mission – to optimize allergy care worldwide. Emerging Societies Program www.worldallergy.org/esp GLORIA Modules WAO offers advice on initiating and Module 1: Allergic Rhinitis developing allergy societies throughout Module 2: Allergic Conjunctivitis the world. This proactive initiative Module 3: Allergic Emergencies aims to expand and improve the Module 4: Immunotherapy specialty of allergy by supporting Module 5: Treatment of Severe Asthma colleagues working in the field of allergy Module 6: Food Allergy worldwide. Through sharing practical experiences and alerting Module 7: Angioedema new societies to the criteria required for WAO membership, Module 8: Anaphylaxis ESM creates relationships with future World Allergy Module 9: Diagnosis of IgE Sensitization Organization member societies, and educates WAO’s leadership Module 10: Chronic Rhinosinusitis and Nasal Polyposis about the challenges and opportunities faced by colleagues in Module 11: Drug Allergy developing countries.

eminars onferences WAO S & C World Allergy Organization Journal www.worldallergy.org/sc www.waojournal.org The Seminars & Conferences World Allergy Organization program invites member Journal is the official societies to apply to host publication of the World a WAO Invited Lecturer. Allergy Organization. An Complementing WAO’s existing international online-only journal, programs, Seminars & Conferences gives World Allergy Organization Journal underscores WAO’s Member Societies the opportunity to bid for an international commitment to raising awareness and advancing excellence in speaker to give a plenary lecture in the scientific program of the clinical care, education, research and training in the field of Society’s annual meeting, on a topic of the Society’s choice. allergy.

WAO Member Societies

National Member Societies Albanian Society of Allergology and Clinical Immunology Italian Association of Territorial and Hospital Allergists American Academy of Allergy, Asthma and Immunology Italian Society for Allergology and Clinical Immunology American College of Allergy, Asthma and Immunology Japanese Society of Allergology Argentine Association of Allergy and Immunology Korean Academy of Allergy, Asthma and Clinical Immunology Argentine Society of Allergy and Immunopathology Latvian Association of Allergists Australasian Society of Clinical Immunology and Allergy Lebanese Society of Allergy and Immunology Austrian Society of Allergology and Immunology Malaysian Society of Allergy and Immunology Azerbaijan Society for Asthma, Allergy and Clinical Immunology Mexican College of Allergy, Asthma and Clinical Immunology Bangladesh Society of Allergy and Immunology Mexican College of Pediatricians Specialized in Allergy and Clinical Belgian Society of Allergology and Immunology Immunology Brazilian Society of Allergy and Immunopathology Mongolian Society of Allergology British Society for Allergy and Clinical Immunology Netherlands Society of Allergology Bulgarian National Society of Allergology Norwegian Society of Allergology and Immunopathology Canadian Society of Allergy and Clinical Immunology Panamanian Association of Allergology and Clinical Immunology Chilean Society of Allergy and Immunology Paraguayan Society of Immunology and Allergy China Allergology Society and Chinese Allergists Peruvian Society of Allergy and Immunology (Chinese) Hong Kong Institute of Allergy Philippine Society of Allergy, Asthma and Immunology Colombian Allergy, Asthma, and Immunology Association Polish Society of Allergology Croatian Society of Allergology and Clinical Immunology Portuguese Society of Allergology and Clinical Immunology Cuban Society of Allergology Romanian Society of Allergology and Clinical Immunology Czech Society of Allergology and Clinical Immunology Russian Association of Allergology and Clinical Immunology Danish Society for Allergology Association of Allergy and Clinical Immunology for Serbia and Egyptian Society of Allergy and Clinical Immunology Montenegro Egyptian Society of Pediatric Allergy and Immunology Singapore Society of Immunology, Allergy & Rheumatology Finnish Society of Allergology and Clinical Immunology Allergy Society of South Africa French Society of Allergology and Clinical Immunology Spanish Society of Allergology and Clinical Immunology Georgian Association of Allergology and Clinical Immunology Swiss Society of Allergology and Immunology German Society for Allergology and Clinical Immunology Allergy and Immunology Society of Thailand Hellenic Society of Allergology and Clinical Immunology Turkish National Society of Allergy and Clinical Immunology Hungarian Society of Allergology and Clinical Immunology Ukrainian Association of Allergologists and Clinical Immunologists Icelandic Society of Allergy and Immunology Uruguayan Society of Allergology Indian College of Allergy, Asthma and Applied Immunology Venezuelan Society of Allergy and Immunology Indonesian Society for Allergy and Immunology Vietnam Association of Allergy, Asthma and Clinical Immunology Israel Association of Allergy and Clinical Immunology Zimbabwe Allergy Society

Associate Member Societies Ecuadorian Society of Allergology and Affiliated Sciences Slovenian Association for Allergology and Clinical Immunology Ecuadorian Society of Allergy and Immunology Allergy & Immunology Society of Sri Lanka Honduran Society of Allergy and Clinical Immunology Swedish Association for Allergology

Regional Organizations Affiliate Organizations The Asia Pacific Association of Allergology and Clinical Immunology International Association of Asthmology Commonwealth of Independent States (CIS Society) European Academy of Allergology and Clinical Immunology Latin American Society of Allergy and Immunology

For WAO membership information please contact the Secretariat World Allergy Orgnanization (WAO) 555 East Wells Street, Suite 1100 • Milwaukee, WI 53202-3823 USA Tel: +1 414 276 1791 • Fax: +1 414 276 3349 e-mail: [email protected] Web site: www.worldallergy.org

March 16, 2008

Dear Colleagues, Welcome to Philadelphia, and to the 31st Symposium in the World Allergy Forum series! The longest-running educational program of the World Allergy Organization has been proud to be part of the AAAAI meeting every year since 1997, when Bill Busse and Larry Lichtenstein chaired our first symposium on the Cellular Mechanisms and Treatment of Allergic Rhinitis. Starting as a program with a focus on allergic rhinitis, World Allergy Forum has broadened over the years to encompass the scientific and clinical aspects of every major topic in allergy that is of interest to the practicing allergist. Our topic today is the Application of Monoclonal Therapies and Therapeutics to Asthma and Allergy. We are starting to gain a good body of experience with the first licensed humanized monoclonal antibody against IgE, with a current indication for use in moderate to severe asthma in adults and adolescents. Will this therapy be safe for use in children, and if so, what considerations will inform our prescription of immunomodulators for pediatric patients? How amenable will other atopic diseases be to treatment with anti-IgE – will we see its application widened for use in allergic rhinoconjunctivitis, anaphylaxis, or eczema? How likely is it that humanized monoclonal antibodies such as anti-IL-5 and anti-TNFa, soluble IL-4 receptors, etc. will become part of our armentarium, and what other monoclonals directed against the cytokines and mediators involved in allergic inflammation are in the pipeline? We are all excited by the theoretical concept of these new directions, but what are the potential problems associated with the clinical use of immunomodulators and biotechnology therapies? Our excellent faculty will guide us through this evolving picture. Shyam Mohapatra will start the session by discussing how monoclonal antibodies are designed. Jean Bousquet will then give us an insight into the pitfalls that may influence the future availability and prescribing of these products. Stephen Holgate will conclude the symposium by considering the future application of monoclonal antibodies to asthma and allergy. It promises to be a great program, and we look forward to your comments and questions. With best regards,

G. Walter Canonica, MD Thomas B. Casale, MD, FAAAAI President President World Allergy Organization American Academy of Allergy, Asthma and Immunology

Designer Drug Design: How are Monoclonal Antibodies Made in 2008?

Shyam S. Mohapatra, PhD FAAAI Mabel & Ellsworth Simmons Professor of Allergy and Immunology VA Hosp & University of South Florida College of Medicine Tampa, FL, United States

Since Paul Ehrlich, who first presented the concept that antibodies and make the new antibody versions carry drugs to their intended could be exploited in therapy, it took four decades before targets. Furthermore, current in vitro antibody generating systems technological advances allowed the exploration of the potential utilize ribosomal display, phage display, yeast surface display, and of antibodies for immunotherapeutic applications. In the late 70s, mammalian cell display, which are capable of generating large and Nobel laureates Kohler and Milstein introduced the monoclonal diverse libraries of clones (1010) expressing several combinations antibody technology, which was further revolutionized by of Fv encoding genes. Depending on the display system, robotics or advances in DNA technology, that led to the ability to tailor and flow cytometry have facilitated the handling of many different clones manipulate the immunoglobulin molecule for specific functions to select those expressing the Fv with promising affinity properties. and in vivo properties. The Fv-encoding genes are mutated using directed mutagenesis approaches – CDR walking, windows mutagenesis, site-directed The ‘state of the art technology’ includes combinatorial mutagenesis, hotspots CDR, and site saturation mutagenesis – or chemistry, DNA mutagenesis, and the ability to fuse “display random mutagenesis approaches – error prone PCR, EvoGene, and and selection” systems in the same setting; which allow DNA shuffling – or a combination of both. Moreover, a plethora physical linking of the mutated gene with its encoded proteins, of in vivo technologies allow antibody engineering at the level of making easier the recovery of the antibody with the desired single cells such as Escherichia coli, mammalian cells or whole properties and specificities. They enable conversion of a mouse- animals. The success of an application of these technologies is derived monoclonal complete antibody (Fc-[Fab]2) to different evident from the recent approval by FDA of the Panitumumab, a combinations or designs of “humanized” versions. These tools fully human antibody directed against the epidermal growth factor allow construction of antibodies comprising just the portion of receptor, which is obtained from transgenic mice expressing human the antibody with the antigen-binding property made up of both antibody repertoires. These technological advances combined with a heavy and light chain (Fv, single chain Fv – scFv) to larger the FDA fast-tracking policy are expected to expand the application engineered arrangements resulting from the multimerization of of these new formats both in diagnostic kits for disease biomarkers these Fv or scFv formats (diabodies, triabodies, tetrabodies). and in therapeutic scenarios. These same tools permit the construction of antibodies or antibody fragments having multiple specificity, which potentially favour the recognition of more than one antigen, the increase in the avidity of the antibody, the cross-activation of immune cells, or bridging an immune cell with its target. The engineering of these formats increase their affinity, stability and clearance time, reduce complications associated to undesirable immune reactions

10 11 12 Adverse Effects in the Application of Biotechnology

Jean Bousquet & Marc Humbert • Anti-CD4 MAb University Hospital and INSERM, Montpellier CD4+ T-cells are likely to be involved as a source of pro-inflammatory and University Hospital, Clamart cytokines in asthma. Keliximab, an anti-CD4 MAb, leads to a Montpellier, France transient reduction in the number of CD4+ T-cells and modulation of CD4+ receptor expression in severe asthmatics. The effects of keliximab may be mediated through a decrease in CD4+ surface Since the 1986 regulatory approval of muromonomab-CD3, a expression and T-lymphocyte numbers, in addition to a reduction in mouse monoclonal antibody (MAb) directed against the T cell CD3ε allergen-induced proliferation (13). However, the clinical effects were antigen, MAbs have become an increasingly important class of modest (14) and the development of the MAb was stopped. therapeutic compounds in a variety of disease areas ranging from cancer, autoimmune, infectious and cardiac diseases as well as • Anti-IL-5 MAb asthma. The limitation of murine mAbs due to immunogenicity was Eosinophilia in atopic diseases and hypereosinophilic syndrome are overcome by replacement of the murine sequences with their human often associated with a high expression of interleukin-5 (IL-5). IL-5 counterpart leading to the development of chimeric, humanized, plays an important role in regulating the production, differentiation, and human therapeutic MAb (1, 2). Remarkable progress has also recruitment, activation, and survival of eosinophils. Therefore, been made following the development of the display technologies, neutralizing IL-5 with an antibody was a promising therapeutic enabling engineering of antibodies with modified properties such strategy in eosinophilic diseases (15). A very large number of animal as molecular size, affinity, specificity, and valency. Moreover, studies proposed that anti-IL-5 MAb could be an effective asthma antibody engineering technologies are constantly advancing to treatment (16). A first study using bronchial challenge did not show enable further tuning of the effector function and serum half life. any efficacy in the late phase reaction and non-specific bronchial Optimal delivery to the target tissue still remains to be addressed hyperreactivity following challenge (17). Mepolizumab treatment to avoid unwanted side effects as a result of systemic treatment does not appear to add significant clinical benefit in patients with while achieving meaningful therapeutic effect. asthma with persistent symptoms despite inhaled corticosteroid therapy (18). These studies may indicate that eosinophil recruitment is Other biological agents-like cytokines and fusion proteins as not only driven by IL-5 (19) or that eosinophils do not have the major treatment modalities for a number of immune mediated and role proposed (20). However, the effects of IL-5 appear to be mainly malignant diseases has also yielded great promise, but there are in the circulation, inducing peripheral mobilization of eosinophils to very few trials in asthma. the circulation without less effect on eosinophil mobilization in the 1- E�f�fcacy�� of biologics: from concept to asthma lungs (21). • Anti-IgE MAb Moreover, the role of anti-IL-5 MAb may not be totally ruled out Immunoglobulin E (IgE) is increasingly recognized as a key since it was found that remodeling may be reduced by anti-IL-5 component of asthma pathophysiology and contributes to both MAb (22). Moreover, in patients with hypereosinophilic syndrome the early- and late-phase inflammatory cascade of the airways by (23) and eosinophilic esophagitis, anti-IL-5 MAb resulted in an inhibiting allergen-induced activation of mast cells. Omalizumab improvement of symptoms (15). Some patients with very high binds free IgE and inhibits mast-cell degranulation. By reducing free eosinophilic inflammation and nasal polyps may also benefit from IgE, omalizumab also downregulates FcεRI on basophils and mast anti-IL-5 MAb (24, 25). Further studies are needed to investigate cells (3-5). These dual effects of omalizumab are important, since the effect of mepolizumab on exacerbation rates, using protocols without FcεRI downregulation almost complete removal of free IgE specifically tailored to patients with asthma with persistent airway would be necessary to elicit functional consequences on mast cells eosinophilia. and basophils. Moreover, unexpectedly, omalizumab considerably • Anti-IL-4 biologics decreases the overall airways inflammation in asthma 6( ). Increases in T helper (Th) 2 cytokine concentrations have been seen in In patients with allergic asthma, omalizumab significantly reduces atopic asthma, with IL-4 and IL-13 thought to have a role in asthma both the early phase and late phase asthmatic response to and studies in animals suggest a role for this target (26). Although allergen challenge (7). A large number of randomized trials initial studies targeting IL-4 were disappointing (27, 28), a new study demonstrated that omalizumab is effective in reducing asthma with a double inhibition may be more promising. Pitrakinra, an IL-4 symptoms and improving quality-of-life while reducing the need variant that targets allergic Th2 inflammation by potently inhibiting for inhaled corticosteroids (8). In patients with severe uncontrolled the binding of IL-4 and IL-13 to IL-4Rα receptor complexes, was found allergic asthma, omalizumab reduces severe exacerbations and to have some effect in phase 2 trials in asthma (29). hospitalizations (9-11), and the biologic is approved by both FDA and EMEA. Moreover, it has been suggested that the effect may persist after treatment (12).

13 Adverse Effects in the Application of Biotechnology

• Anti-TNFα biologics TNF–α antagonists (infliximab, etanercept, adalimumab) are It has been suggested that some of the features of severe asthma widely used in rheumatoid arthritis and several other inflammatory might be due to upregulation of the tumor necrosis factor-α (TNF-α) diseases. Both immediate and delayed adverse reactions have pathway. In support of this, studies have shown that severe asthma been described, suggesting type I and T cell-mediated mechanisms is associated with an increased presence of TNF-α within the (36). These reactions even occur in children (37). Mild to moderate airway and an increase in TNF-α expression on peripheral blood reactions following injection occur in 29.3% patients with etanercept mononuclear cells. Moreover, TNF-α has the ability to induce several (38) and 15.3% with adalimumab (39, 40). Some studies describe of the pro-inflammatory changes associated with severe asthma, histological findings of a cell-mediated Th1 reaction, with CD8+ T including neutrophilic inflammation 3( 0). Interest in the role of TNF-α cells composing the majority of the dermal infiltrate 41( ). Histological in severe asthma has increased following a small cross-over clinical features of eosinophilic cellulitis as a response to etanercept suggest trial (31) and an open study which have suggested that ethanercept a Th2-mediated phenomenon (42). Immediate positive skin tests is effective in asthma (32). However, a large randomized clinical against ethanercept have only been demonstrated recently (43). trial using golumimab in patients with severe asthma did not confirm Adalimumab, a human mAb against TNF-α, was not found to these optimistic results. induce anaphylactic reactions and can be used in patients allergic to infliximab 44( ). However, delayed type reactions were observed 2- Safety of biologics using intra-dermal skin tests (43). Biological agents-like cytokines, MAb and fusion proteins can cause a great variety of adverse side-effects. Based on the peculiar features of Like nearly all systemic cancer therapies, MAbs are associated with biological agents a new classification of these adverse side-effects of hypersensitivity reactions (45). Severe hypersensitivity reactions biological agents was proposed - related but clearly distinct from the are rare, with an incidence of ≤ 5%. Reactions to taxanes and classification of side-effects observed with chemicals and drugs. This monoclonal antibodies are generally immediate, occurring during the classification differentiated five distinct types, namely clinical reactions first few minutes of the first or second infusion. However,1 0%-30% because of high cytokine levels (type α), hypersensitivity because of an of reactions to MAbs are delayed, and may occur in later infusions, immune reaction against the biological agent (ß), immune or cytokine indicating the importance of close observation of the patient following imbalance syndromes (γ), symptoms because of cross-reactivity (δ) and administration. Mild-to-moderate reactions can be managed by symptoms not directly affecting the immune system (ε) (33) (Figure 1). temporary infusion interruption, reduction of the infusion rate, and This classification could help to better deal with the clinical features symptom management. Rechallenge should be considered after of these side-effects, to identify possible individual and general risk complete resolution of all symptoms. Severe reactions may require factors and to direct research in this novel area of medicine. treatment discontinuation.

• Hypersensitivity reactions Cetuximab, a chimeric anti-epidermal growth factor receptor MAb Monoclonal antibodies can be derived from several sources: murine currently used to treat metastatic colorectal cancer, is often associated antibodies (e.g. OKT-3), chimeric (e.g. infliximab), humanized (e.g. with hypersensitivity reactions (46). Although cutaneous manifestations omalizumab) or human (e.g. adalimumab). Two forms of reactions are the most common toxicities associated with cetuximab, they are have been identified: acute and delayed. They appear to be related to rarely life-threatening. In a small controlled study, the reaction rate the presence of antibodies to the MAb (against murine (34) or human was 22% and significantly higher than the rate noted in any large components), but many reactions do not appear to be anaphylactic published trial. In this study, all reactions occurred during the first dose (IgE mediated) (33, 35). and there was a strong relationship between prior allergy history and chance of reaction (47).

Figure 1: Classification of adverse side effects of biological agents (33)

14 Adverse Effects in the Application of Biotechnology

Risk of anaphylaxis was included in the US and EU prescribing Immune imbalance information for omalizumab (anti-IgE MAb), but the nature of these Biologics that suppress the immune system such as TNF-α blocking reactions needed further elaboration. A review of spontaneous drugs are associated with immune imbalance and induce minor postmarketing adverse event reports submitted to the US Food and infections of the urinary tract, respiratory tract and sinuses, and with Drug Administration's Adverse Event Reporting System database serious infections such as tuberculosis, sepsis (bacteria in the blood) and to the manufacturers of omalizumab and cases published in and fungal infections (Table 2) shown on next page. Individuals the literature was done through December 2006 (48). Diagnostic with active infections should not be treated with TNF-α blocking criteria for anaphylaxis outlined by the National Institute of Allergy biologics. Some patients who used TNF-α blocking biologics and Infectious Diseases and the Food Allergy and Anaphylaxis developed cancer. In a study in severe asthma, golimumab-treated patients experienced serious adverse events, infections were the Network were used to screen cases. 124 cases of anaphylaxis most common adverse events. One patient died from sepsis and associated with omalizumab administration in 57,300 patients some malignancies occurred. with asthma were identified (0.2%). Many cases had a delayed onset of symptoms beyond 2 hours after dose administration. Many • Parasitic infections cases were also characterized by a protracted progression, with Although the role of IgE in immunity against helminth parasites is individual signs and symptoms of anaphylaxis staggered over unclear, there is concern that omalizumab may be unsafe in subjects hours. Review of the case reports did not reveal any predictive at risk of helminth infection. An exploratory study was conducted in risk factors for the delayed onset or protracted progression of Brazil to investigate the safety of omalizumab in subjects with allergic anaphylaxis. asthma and/or allergic rhinitis at high risk of intestinal helminth infection (53). 137 subjects (12-30 years) at high risk of geohelminth The American Academy of Allergy, Asthma & Immunology and the infection received pre-study anthelmintic treatment, followed by 52 American College of Allergy, Asthma and Immunology Executive weeks’ treatment with omalizumab or placebo. Of the omalizumab Committees formed the Omalizumab Joint Task Force (OJTF) subjects 50% experienced at least one intestinal geohelminth with the purpose of reviewing the omalizumab clinical trials and infection compared with 41% of placebo subjects, providing some postmarketing surveillance data on anaphylaxis and anaphylactoid evidence for a potential increased incidence of geohelminth infection reactions (49). Using the definition of anaphylaxis proposed in subjects receiving omalizumab. Omalizumab therapy was well at a 2005 multidisciplinary symposium (50), the Omalizumab tolerated, and did not appear to be associated with increased Joint Task Force concluded that 35 patients had 41 episodes of morbidity attributable to intestinal helminths as assessed by clinical anaphylaxis associated with omalizumab administration between and laboratory adverse events, maximal helminth infection intensities June 1, 2003, and December 31, 2005. With 39,510 patients and additional anthelmintic requirements. Time to first infection was receiving omalizumab during the same period of time, this would similar between treatment groups. Infection severity and response to correspond to an anaphylaxis-reporting rate of 0.09% of patients. anthelmintics appeared to be unaffected by omalizumab therapy. Thus, omalizumab induces very few anaphylactic reactions by comparison to other biologics. Of those 36 events for which the 3- Immune tolerance time of reaction was known, 22 (61%) reactions occurred in the first Infliximab, a human-murine chimeric monoclonal IgG antibody 2 hours after one of the first3 doses. Five (14%) of the events after against TNF-α effective in rheumatoid arthritis and other the fourth or later doses occurred within 30 minutes. Considering inflammatory diseases. With repeated infusions, however, the the timing of these 36 events, an observation period of 2 hours formation of neutralizing anti-infliximab antibodies becomes a for the first 3 injections and 30 minutes for subsequent injections problem, necessitating increased doses or more frequent drug would have captured 75% of the anaphylactic reactions. administration and sometimes necessitating discontinuation of therapy because of secondary response failure and/or infusion- These reactions have lead to a proposed modification of the related side effects; this has been observed both in rheumatoid administration of omalizumab (49). The OJTF report provides arthritis patients and in patients with other immunoinflammatory recommendations for physicians who prescribe Xolair (omalizumab) diseases. In clinical practice, however, patients with RA or any on the suggested wait periods after administration and patient other chronic inflammatory disease treated with infliximab may differ education regarding anaphylaxis (Table 1) shown on next page. considerably from the average patient in randomized clinical trials (54, 55). Trough serum infliximab levels after the first2 intravenous • Serum sickness infusions of infliximab at 3 mg/kg varied considerably between Monoclonal antibodies which induce the formation of IgG antibodies patients (range 0-22 g/ml). At this stage, only 13% of the patients can potentially activate complement and lead to serum sickness (51). were anti-infliximab antibody positive. With subsequent infusions, Omalizumab does not usually activate complement and only one the frequency of antibody positivity rose to 30% and 44% (at 3 reaction of serum sickness has been described (52). months and 6 months, respectively), accompanied by diminished trough levels of infliximab. Indeed, low infliximab levels at 1.5 15 Adverse Effects in the Application of Biotechnology months predicted antibody development and later treatment failure. 1- Costs There were highly significant correlations between high levels of All biologics are very expensive treatments and many are not antibodies and later dose increases, side effects, and cessation of devoid of side effects. Thus, the patients treated should be perfectly therapy. Adalimumab is well tolerated and appears to be effective characterized and biologics only administered if they can reduce in maintaining clinical remission in patients with bowel disease severe symptoms and reduce hospitalizations. This is the case for and lost response to infliximab (56, 57). omalizumab which is indicated in severe uncontrolled asthmatics despite the use of optimal therapy. However, even in these patients, Certolizumab pegol is a pegylated humanized Fab’ fragment with the costs of treatment need to be scrutinized. It has been shown that a high binding affinity for TNF-α. Antinuclear antibodies developed omalizumab is cost-effective in some but not all studies (59-61). in 8% of the patients in the certolizumab group; antibodies against However, since this treatment can reduce severe exacerbations certolizumab pegol developed in 9% of treated patients (58). and improve quality-of-life, it is indicated in patients with severe Such a tolerance has not been reported yet for omalizumab. uncontrolled asthma despite optimal pharmacotherapy.

Table 1: Summary of AAAAI/ACAAI OJTF recommendations concerning omalizumab use (49)

Table 2: Classification of side effects of anti-TNF-α biologics (33)

16 Adverse Effects in the Application of Biotechnology

References 1. Lonberg N. Human monoclonal antibodies from transgenic mice. Handb Exp 22. Flood-Page P, Menzies-Gow A, Phipps S, Ying S, Wangoo A, Ludwig MS, Pharmacol. 2008(181):69-97. et al. Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics. J Clin Invest. 2003 2. Nissim A, Chernajovsky Y. Historical development of monoclonal antibody Oct;112(7):1029-36. therapeutics. Handb Exp Pharmacol. 2008(181):3-18. 23. Plotz SG, Simon HU, Darsow U, Simon D, Vassina E, Yousefi S, et al. Use of an 3. MacGlashan D. Loss of receptors and IgE in vivo during treatment with anti-IgE anti-interleukin-5 antibody in the hypereosinophilic syndrome with eosinophilic antibody. J Allergy Clin Immunol. 2004 Dec;114(6):1472-4. dermatitis. N Engl J Med. 2003 Dec 11;349(24):2334-9. 4. Beck LA, Marcotte GV, MacGlashan D, Togias A, Saini S. Omalizumab-induced 24. Gevaert P, Lang-Loidolt D, Lackner A, Stammberger H, Staudinger H, Van Zele reductions in mast cell Fce psilon RI expression and function. J Allergy Clin T, et al. Nasal IL-5 levels determine the response to anti-IL-5 treatment in patients Immunol. 2004 Sep;114(3):527-30. with nasal polyps. J Allergy Clin Immunol. 2006 Nov;118(5):1133-41. 5. Holgate S, Casale T, Wenzel S, Bousquet J, Deniz Y, Reisner C. The anti- 25. Rinia AB, Kostamo K, Ebbens FA, van Drunen CM, Fokkens WJ. Nasal inflammatory effects of omalizumab confirm the central role of IgE in allergic polyposis: a cellular-based approach to answering questions. Allergy. 2007 inflammation. J Allergy Clin Immunol.2 005 Mar;115(3):459-65. Apr;62(4):348-58. 6. Djukanovic R, Wilson SJ, Kraft M, Jarjour NN, Steel M, Chung KF, et al. 26. Ma Y, Hayglass KT, Becker AB, Halayko AJ, Basu S, Simons FE, et al. Novel Effects of treatment with anti-immunoglobulin E antibody omalizumab on cytokine peptide-based vaccines: an interleukin-4 vaccine suppresses airway airway inflammation in allergic asthma. Am J Respir Crit Care Med. 2004 allergic responses in mice. Allergy. 2007 Jun;62(6):675-82. Sep 15;170(6):583-93. 27. Borish LC, Nelson HS, Corren J, Bensch G, Busse WW, Whitmore JB, et al. 7. Fahy JV. Anti-IgE: lessons learned from effects on airway inflammation and Efficacy of soluble IL-4 receptor for the treatment of adults with asthma. J Allergy asthma exacerbation. J Allergy Clin Immunol. 2006 Jun;117(6):1230-2. Clin Immunol. 2001 Jun;107(6):963-70. 8. Holgate ST, Djukanovic R, Casale T, Bousquet J. Anti-immunoglobulin E treatment 28. Borish LC, Nelson HS, Lanz MJ, Claussen L, Whitmore JB, Agosti JM, et al. with omalizumab in allergic diseases: an update on anti-inflammatory activity Interleukin-4 receptor in moderate atopic asthma. A phase I/II randomized, and clinical efficacy. Clin Exp Allergy.2 005 Apr;35(4):408-16. placebo-controlled trial. Am J Respir Crit Care Med. 1999 Dec;160(6):1816- 9. Bousquet J, Cabrera P, Berkman N, Buhl R, Holgate S, Wenzel S, et al. The effect 23. of treatment with omalizumab, an anti-IgE antibody, on asthma exacerbations 29. Wenzel S, Wilbraham D, Fuller R, Getz EB, Longphre M. Effect of an and emergency medical visits in patients with severe persistent asthma. Allergy. interleukin-4 variant on late phase asthmatic response to allergen challenge 2005 Mar;60(3):302-8. in asthmatic patients: results of two phase 2a studies. Lancet. 2007 Oct 10. Bousquet J, Rabe K, Humbert M, Chung KF, Berger W, Fox H, et al. Predicting 20;370(9596):1422-31. and evaluating response to omalizumab in patients with severe allergic asthma. 30. Heffler E, Berry M, Pavord ID. Tumor necrosis factor-alpha: a promising Respir Med. 2007 Jul;101(7):1483-92. therapeutic target for asthma? BioDrugs. 2007;21(6):345-9. 11. Humbert M, Beasley R, Ayres J, Slavin R, Hebert J, Bousquet J, et al. Benefits of 31. Berry MA, Hargadon B, Shelley M, Parker D, Shaw DE, Green RH, et al. omalizumab as add-on therapy in patients with severe persistent asthma who Evidence of a role of tumor necrosis factor alpha in refractory asthma. N Engl are inadequately controlled despite best available therapy (GINA 2002 step J Med. 2006 Feb 16;354(7):697-708. 4 treatment): INNOVATE. Allergy. 2005 Mar;60(3):309-16. 32. Howarth PH, Babu KS, Arshad HS, Lau L, Buckley M, McConnell W, et al. 12. Nopp A, Johansson SG, Ankerst J, Palmqvist M, Oman H. CD-sens and clinical Tumour necrosis factor (TNFalpha) as a novel therapeutic target in symptomatic changes during withdrawal of Xolair after 6 years of treatment. Allergy. 2007 corticosteroid dependent asthma. Thorax. 2005 Dec;60(12):1012-8. Oct;62(10):1175-81. 33. Pichler WJ. Adverse side-effects to biological agents. Allergy. 2006 13. Kon OM, Sihra BS, Loh LC, Barkans J, Compton CH, Barnes NC, et al. The Aug;61(8):912-20. effects of an anti-CD4 monoclonal antibody, keliximab, on peripheral blood CD4+ T-cells in asthma. Eur Respir J. 2001 Jul;18(1):45-52. 34. Georgitis JW, Browning MC, Steiner D, Lorentz WB. Anaphylaxis and desensitization to the murine monoclonal antibody used for renal graft rejection. 14. Kon OM, Sihra BS, Compton CH, Leonard TB, Kay AB, Barnes NC. Randomised, Ann Allergy. 1991 Apr;66(4):343-7. dose-ranging, placebo-controlled study of chimeric antibody to CD4 (keliximab) in chronic severe asthma. Lancet. 1998 Oct 3;352(9134):1109-13. 35. Cheifetz A, Mayer L. Monoclonal antibodies, immunogenicity, and associated infusion reactions. Mt Sinai J Med. 2005 Jul;72(4):250-6. 15. Simon D, Braathen LR, Simon HU. Anti-interleukin-5 antibody therapy in eosinophilic diseases. Pathobiology. 2005;72(6):287-92. 36. Campi P, Benucci M, Manfredi M, Demoly P. Hypersensitivity reactions to biological agents with special emphasis on tumor necrosis factor-alpha 16. Pauwels RA, Brusselle GJ, Kips JC. Cytokine manipulation in animal models of antagonists. Curr Opin Allergy Clin Immunol. 2007 Oct;7(5):393-403. asthma. Am J Respir Crit Care Med. 1997 Oct;156(4 Pt 2):S78-81. 37. Kolho KL, Ruuska T, Savilahti E. Severe adverse reactions to Infliximab therapy 17. Leckie MJ, ten Brinke A, Khan J, Diamant Z, O’Connor BJ, Walls CM, et al. are common in young children with inflammatory bowel disease. Acta Paediatr. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway 2007 Jan;96(1):128-30. hyper-responsiveness, and the late asthmatic response. Lancet. 2000 Dec 23- 30;356(9248):2144-8. 38. Dore RK, Mathews S, Schechtman J, Surbeck W, Mandel D, Patel A, et al. The immunogenicity, safety, and efficacy of etanercept liquid administered 18. Flood-Page P, Swenson C, Faiferman I, Matthews J, Williams M, Brannick once weekly in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2007 L, et al. A study to evaluate safety and efficacy of mepolizumab in patients Jan-Feb;25(1):40-6. with moderate persistent asthma. Am J Respir Crit Care Med. 2007 Dec 1;176(11):1062-71. 39. Weinblatt ME, Keystone EC, Furst DE, Kavanaugh AF, Chartash EK, Segurado OG. Long term efficacy and safety of adalimumab plus methotrexate in patients 19. Rosenberg HF, Phipps S, Foster PS. Eosinophil trafficking in allergy and asthma. with rheumatoid arthritis: ARMADA 4 year extended study. Ann Rheum Dis. J Allergy Clin Immunol. 2007 Jun;119(6):1303-10; quiz 11-2. 2006 Jun;65(6):753-9. 20. O’Byrne PM. The demise of anti IL-5 for asthma, or not. Am J Respir Crit Care 40. Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH, Birbara Med. 2007 Dec 1;176(11):1059-60. CA, et al. Adalimumab, a fully human anti-tumor necrosis factor alpha 21. van Rensen EL, Stirling RG, Scheerens J, Staples K, Sterk PJ, Barnes PJ, et al. monoclonal antibody, for the treatment of rheumatoid arthritis in patients Evidence for systemic rather than pulmonary effects of interleukin-5 administration taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 2003 in asthma. Thorax. 2001 Dec;56(12):935-40. Jan;48(1):35-45. 17 Adverse Effects in the Application of Biotechnology

41. Zeltser R, Valle L, Tanck C, Holyst MM, Ritchlin C, Gaspari AA. Clinical, 52. Pilette C, Coppens N, Houssiau FA, Rodenstein DO. Severe serum sickness-like histological, and immunophenotypic characteristics of injection site reactions syndrome after omalizumab therapy for asthma. J Allergy Clin Immunol. 2007 associated with etanercept: a recombinant tumor necrosis factor alpha receptor: Oct;120(4):972-3. Fc fusion protein. Arch Dermatol. 2001 Jul;137(7):893-9. 53. Cruz AA, Lima F, Sarinho E, Ayre G, Martin C, Fox H, et al. Safety of anti- 42. Winfield H, Lain E, Horn T, Hoskyn J. Eosinophilic cellulitislike reaction to immunoglobulin E therapy with omalizumab in allergic patients at risk of subcutaneous etanercept injection. Arch Dermatol. 2006 Feb;142(2):218- geohelminth infection. Clin Exp Allergy. 2007 Feb;37(2):197-207. 20. 54. Bendtzen K, Geborek P, Svenson M, Larsson L, Kapetanovic MC, Saxne 43. Benucci M, Manfredi M, Demoly P, Campi P. Injection site reactions to TNF-alpha T. Individualized monitoring of drug bioavailability and immunogenicity in blocking agents with positive skin tests. Allergy. 2008 Jan;63(1):138-9. rheumatoid arthritis patients treated with the tumor necrosis factor alpha inhibitor infliximab. Arthritis Rheum.2 006 Dec;54(12):3782-9. 44. Youdim A, Vasiliauskas EA, Targan SR, Papadakis KA, Ippoliti A, Dubinsky MC, et al. A pilot study of adalimumab in infliximab-allergic patients. Inflamm Bowel 55. Svenson M, Geborek P, Saxne T, Bendtzen K. Monitoring patients treated Dis. 2004 Jul;10(4):333-8. with anti-TNF-alpha biopharmaceuticals: assessing serum infliximab and anti- infliximab antibodies. Rheumatology (Oxford). 2007 Dec;46(12):1828-34. 45. Lenz HJ. Management and preparedness for infusion and hypersensitivity reactions. Oncologist. 2007 May;12(5):601-9. 56. Peyrin-Biroulet L, Laclotte C, Bigard MA. Adalimumab maintenance therapy for Crohn’s disease with intolerance or lost response to infliximab: an open-label 46. Patel DD, Goldberg RM. Cetuximab-associated infusion reactions: pathology study. Aliment Pharmacol Ther. 2007 Mar 15;25(6):675-80. and management. Oncology (Williston Park). 2006 Oct;20(11):1373-82; discussion 82, 92-4, 97. 57. Peyrin-Biroulet L, Laclotte C, Roblin X, Bigard MA. Adalimumab induction therapy for ulcerative colitis with intolerance or lost response to infliximab: an open-label 47. O’Neil BH, Allen R, Spigel DR, Stinchcombe TE, Moore DT, Berlin JD, et al. study. World J Gastroenterol. 2007 Apr 28;13(16):2328-32. High incidence of cetuximab-related infusion reactions in Tennessee and North Carolina and the association with atopic history. J Clin Oncol. 2007 Aug 58. Schreiber S, Khaliq-Kareemi M, Lawrance IC, Thomsen OO, Hanauer SB, 20;25(24):3644-8. McColm J, et al. Maintenance therapy with certolizumab pegol for Crohn’s disease. N Engl J Med. 2007 Jul 19;357(3):239-50. 48. Limb SL, Starke PR, Lee CE, Chowdhury BA. Delayed onset and protracted progression of anaphylaxis after omalizumab administration in patients with 59. Brown R, Turk F, Dale P, Bousquet J. Cost-effectiveness of omalizumab in patients asthma. J Allergy Clin Immunol. 2007 Dec;120(6):1378-81. with severe persistent allergic asthma. Allergy. 2007 Feb;62(2):149-53. 49. Cox L, Platts-Mills TA, Finegold I, Schwartz LB, Simons FE, Wallace DV. American 60. Krishnan JA, Gould M. Omalizumab for severe allergic asthma: dollars and Academy of Allergy, Asthma & Immunology/American College of Allergy, sense. J Allergy Clin Immunol. 2007 Nov;120(5):1015-7. Asthma and Immunology Joint Task Force Report on omalizumab-associated anaphylaxis. J Allergy Clin Immunol. 2007 Dec;120(6):1373-7. 61. Wu AC, Paltiel AD, Kuntz KM, Weiss ST, Fuhlbrigge AL. Cost-effectiveness of omalizumab in adults with severe asthma: results from the Asthma Policy Model. 50. Sampson HA, Munoz-Furlong A, Bock SA, Schmitt C, Bass R, Chowdhury BA, J Allergy Clin Immunol. 2007 Nov;120(5):1146-52. et al. Symposium on the definition and management of anaphylaxis: summary report. J Allergy Clin Immunol. 2005 Mar;115(3):584-91. 51. Rutgeerts P, Van Assche G, Vermeire S. Review article: Infliximab therapy for inflammatory bowel disease--seven years on. Aliment Pharmacol Ther. 2006 Feb 15;23(4):451-63.

18 19 20 21 22 23 24 25 26 27 28 29 30 The Future Application of Monoclonal Antibodies to Asthma and Allergy

Stephen T. Holgate chemically coupled to limpet haemocyanin and the other in which Infection, Inflammation and Repair Division a 14-amino-acid peptide from IL-4 is inserted into variant hepatitis Southampton General Hospital B virus core antigen. Both vaccines induced high antibody titres Southampton, United Kingdom specific for mouse IL-4 and inhibited antigen-induced lung inflammation. However, using co-stimulation blockade in a mouse model of allergy to grass pollen, it was reported that the secondary Allergic diseases have reached epidemic proportions worldwide. IgE response is not T-cell dependent, thereby raising doubts over An understanding of the cellular and soluble mediators that are the usefulness of IL‑4 blockade for treating established allergic involved in allergic inflammatory responses not only helps in disease. The numerous functions of IL-13 in regulating IgE understanding the mechanisms of current treatments, but is also production, eosinophilic inflammation, airway smooth-muscle important for the identification of new targets that are amenable hyperplasia, the induction of goblet-cell hyperplasia with mucus to both small-molecule and biological interventions. It is the production, and the recruitment of monocytes, macrophages and introduction of monoclonal antibodies and soluble cytokine T cells into the airway spaces make it a key therapeutic target in receptors that is revolutionising approaches to the treatment of allergy and asthma. IL-13 binds to a low-affinity IL-13Rα1 subunit asthma and allergy however, when compared to other areas of and a high-affinity complex comprised of IL-13Rα1 and IL-4Rα. chronic inflammation; development of biologics in our field has Binding to this high-affinity complex leads to the phosphorylation- been slow with the exception of immunotherapy. The successful dependent activation of Janus kinase 1 (JAK1), JAK2 and STAT6. introduction of omalizumab for severe allergic asthma has IL-4Rα also stabilizes the binding of IL-13 to its receptor to augment stimulated great interest in this approach, but even with this IL-13-mediated responses. However, a non-signalling, high-affinity humanised monoclonal antibody, cost effectiveness analyses are IL-13-binding chain, IL-13Rα2, strongly inhibits the activity of IL-13. restricting its use even though it has passed scrutiny by such agents Selective blockade of IL-13 has been achieved in mice using a as the National Institute of Health & Clinical Excellence in the soluble form of IL-13Rα2, which competes for binding to IL-13 UK. The need for 16 weeks therapy before a decision can be but not to IL4, and this led to the reversal of airway hyper- made to separate responders from non responders emphasises responsiveness and mucus production in allergen exposed the need for biomarkers of response since patients vary greatly sensitized mice. A soluble form of IL-13Rα2 that binds IL-13 with in their response to this treatment. Understanding the underlying 100-fold greater affinity than does IL-13Rα1 is present in mouse mechanisms of allergic disease has stimulated the further but not human serum. Antagonizing the effects of IL-13 could also development of a series of biologics targeted towards critical be achieved by administering soluble IL-13 receptors or IL-13R- cells and molecules in the allergic cascade presented below. specific monoclonal antibodies. In cynomolgus monkeys sensitized Because of the sentinel role that Th2 cytokines have in orchestrating to Ascaris suum and then challenged with antigen from this allergic inflammation, they and their receptors are key therapeutic nematode , a mouse antibody specific for human IL-13 (mAb13.2) targets. Both IL-4 and IL-13 have a crucial role in the immunoglobulin and the humanized counterpart (IMA-638) inhibited eosinophil isotype switching of B cells to produce IgE, whereas IL-4 alone and neutrophil influx into the lungs as assessed by bronchoalveolar is crucial for maintaining the Th2-cell phenotype, which makes lavage. Phase I trials of the IL-13-specific monoclonal antibody both cytokines attractive therapeutic targets. A large number of CAT-354 in 34 mildly asthmatic patients have been successfully animal studies have shown that blocking production or inhibiting completed and Phase II trials are in progress. Subcutaneous or the effects of IL-4 has profound effects on the allergic phenotype. inhaled pitrakinra, a mutant IL-4 protein that inhibits the binding A soluble, recombinant, human IL-4 receptor (altrakincept) consists of IL-4 and IL-13 to IL-4Rα complexes, has recently shown efficacy of the extracellular portion of human IL-4Rα and is non- in the treatment of allergen-induced asthma. A novel, recombinant immunogenic. A small proof-of-concept trial of nebulized inhaled IL-13 peptide-based vaccine has also been shown to reduce altrakincept for 12 weeks in patients with mild to moderate asthma allergic inflammatory responses in mice. Rodent and non-human indicated efficacy by allowing withdrawal from treatment with primate studies have indicated an important role for IL-5 in various inhaled corticosteroids without relapse, and this result was models of asthma. Inhaled IL-5 modulates the number of eosinophil subsequently confirmed in a larger trial. However, a Phase III trial progenitors in both the airways and bone marrow of asthmatic failed to confirm the efficacy of altrakincept for the treatment of individuals and induces local eosinophilia in non-asthmatic asthma. This trial does not invalidate IL-4 as a target for the individuals. Two humanized, human-IL-5-specific monoclonal treatment of allergy and asthma, as there were concerns over the antibodies, Sch-55,700 and mepolizumab (SB-240,563), have bioavailability of altrakincept in this study. Further Phase II studies been developed for the treatment of asthma. In a small double- are in progress using humanized IL-4-specific and IL-4Rα-blocking blind trial, mepolizumab produced a rapid dose-dependent antibodies such as pascolizumab (SB240, 683). Two vaccines reduction in the number of circulating and sputum eosinophils that against IL-4 have been tested in mice, one in which IL-4 is 31 The Future Application of Monoclonal Antibodies to Asthma and Allergy

persisted for 3 months but, surprisingly, this had no effect on either targets that have been largely identified in mouse models of antigen the late asthmatic response or on airway hyper-responsiveness. In driven allergic type inflammation include IL-15, IL-17A, IL-17E (or a group of patients with severe persistent asthma, treatment with IL-25), IL-33, IL-31, IL-21 and thymic stromal lymphopoietin (TSLP) Sch-55,700 resulted in a decrease in the number of blood which are all proposed to enhance inflammatory responses. The eosinophils, but over the course of 10 weeks it had no effect on engineering of monoclonal antibodies to include fully humanised any measures of asthma outcome, an observation that has recently molecules as well as antibody engineering to enhance certain been confirmed in a large trial with mepolizumab. A further study properties such as antibody dependant cell cytotoxicity involving using mepolizumab confirmed the persistent suppression of activation of NK cells created when the fucose-linked carbohydrate eosinophilia in blood, bone marrow and airway lavage, but in chain of the Fc portion of the antibody is removed, greatly enhances airway biopsies, there was only a 55% reduction in the number the potential of these agents as therapeutics so that whole cell of tissue eosinophils. As a proportion of eosinophils in the airways populations can be eliminated rather than simply blunting their of patients with asthma lack IL-5R, it was suggested that this might function. explain the apparent lack of clinical efficacy of targeting IL-5. IL-5 could have more subtle effects on asthmatic airways - for example, References 1. Stephen T. Holgate and Riccardo Polosa Treatment strategies for allergy and mepolizumab treatment decreases immunostaining for tenascin, asthma. Nature Immunology Reviews 2008; 8: 1-13. lumican and procollagen III in the bronchial mucosal subepithelial 2. Flood-Page P, Swenson C, Faiferman I, Matthews J, Williams M, Brannick basal lamina and in allergen challenged skin. In addition, IL-5- L, Robinson D, Wenzel S, Busse W, Hansel TT, Barnes NC; International Mepolizumab Study Group. A study to evaluate safety and efficacy of specific treatment resulted in a parallel decrease in the number of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care airway eosinophils expressing mRNA for TGFβ1 and of TGFβ1 Med. 2007 Dec 1;176(11):1062-71. levels in bronchoalveolar-lavage fluid, which indicates a possible 3. Bree A, Schlerman FJ, Wadanoli M, Tchistiakova L, Marquette K, Tan XY, role for IL-5 in airway remodelling. In contrast to asthma, Jacobson BA, Widom A, Cook TA, Wood N, Vunnum S, Krykbaev R, Xu X, Donaldson DD, Goldman SJ, Sypek J, Kasaian MT. IL-13 blockade reduces lung mepolizumab is highly efficacious in the treatment of inflammation after Ascaris suum challenge in cynomolgus monkeys. J Allergy hypereosinophilic syndrome and eosinophilic oesophagitis, but Clin Immunol. 2007 May;119(5):1251-7. not atopic dermatitis. A therapeutic DNA-based vaccine against 4. Holgate ST. The epithelium takes centre stage in asthma and atopic dermatitis. IL-5 is also being developed. As asthma becomes more severe Trends Immunol. 2007 Jun;28(6):248-51. and aggressive it adopts a Th2 cytokine profile with enhanced 5. Satoh M, Iida S, Shitara K. Non-fucosylated therapeutic antibodies as next generation therapeutic antibodies. Expert Opin Biol Ther. 2006 Nov;6(11): production of IFN-γ and TNFα. Both in mouse models and in 3 -73. small clinical trials in severe asthma anti-TNF therapies (etanercept, infliximab) were reported to be efficacious. However in a large RCT involving over 300 patients with severe asthma, treated with golimumab (CNTO 148) for 52 weeks efficacy for baseline lung function and asthma exacerbations was not apparent. However, a subgroup analysis indicated that reversibility of lung function, late onset disease and concurrent sinusitis were predictors of efficacy and further trials in this subpopulation are now being undertaken. Blocking the actions of IL-9 reduces allergen-induced airway inflammation and airway hyper-responsiveness in mouse models. Two Phase I dose-escalation studies of an IL-9-specific monoclonal antibody (MEDI-528) in healthy volunteers have been completed without problems. Phase II trials are in progress for treating symptomatic, moderate to severe, persistent asthma. IL-2 is intimately involved in T cell activation and its α receptor (CD25) has been targeted with a monoclonal antibody Daclizumab that is efficacious in preventing renal transplant rejection. A phase IIa clinical trial in moderate-severe asthma has also revealed efficacy on the basis that activated T cells contribute to ongoing disease activity. As new targets for immunologics are discovered it is important that appropriate trial designs are used to test them taking account of markers of response and surrogate endpoints that include the identification of biomarkers. Some examples of novel

32 The Future Application of Monoclonal Antibodies to Asthma and Allergy

33 34 35 36 37 38 39 40 41 42 43 Notes

WAO-0108-612 www.worldallergy.org Fax: +14142763349 Tel: +14142761791 USA Milwaukee, WI53202-3823 555 EastWells Street,Suite1100 World AllergyOrganization(WAO)

g r o . y g r e l l a d l r o w . w w w www.worldallergy.org